Summary The neural growth factors known as neurotrophins are hypothesized to play central roles in sleep homeostasis; an enigmatic process that regulates sleep need. Brain neurotrophin mRNA and protein levels increase with wakefulness and administration of exogenous neurotrophin increases sleep time and indices of sleep intensity. Neurotrophins are secreted by active neurons where they can act globally throughout the brain, or locally in a use-dependent fashion. Neurotrophins also govern cellular processes linked to sleep function including brain cell survival and synaptic plasticity. Nevertheless, the precise role of neurotrophins in sleep and sleep regulation is unclear. This is because previous investigations have relied on non-selective pharmacological agents, non-physiological neurotrophin concentrations, or are principally correlational in nature. We will more precisely determine the role of neurotrophins in sleep regulation using a novel chemo-genetic technique that allows for rapid and reversible inhibition of all three neurotrophin-TrK receptors in vivo. This is accomplished using transgenic mice with knock-in TrKA, B or C receptors that are potently inhibited in the presence of a small, brain permeable molecule. We will use this model to determine the role of each TrK receptor in sleep homeostasis and genome-wide changes in mRNA expression that accompany the accumulation and discharge of sleep need.